PMID- 27613445
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200225
IS  - 1474-9726 (Electronic)
IS  - 1474-9718 (Print)
IS  - 1474-9718 (Linking)
VI  - 15
IP  - 6
DP  - 2016 Dec
TI  - A comprehensive approach to the molecular determinants of lifespan using a 
      Boolean model of geroconversion.
PG  - 1018-1026
LID - 10.1111/acel.12504 [doi]
AB  - Altered molecular responses to insulin and growth factors (GF) are responsible 
      for late-life shortening diseases such as type-2 diabetes mellitus (T2DM) and 
      cancers. We have built a network of the signaling pathways that control S-phase 
      entry and a specific type of senescence called geroconversion. We have translated 
      this network into a Boolean model to study possible cell phenotype outcomes under 
      diverse molecular signaling conditions. In the context of insulin resistance, the 
      model was able to reproduce the variations of the senescence level observed in 
      tissues related to T2DM's main morbidity and mortality. Furthermore, by 
      calibrating the pharmacodynamics of mTOR inhibitors, we have been able to 
      reproduce the dose-dependent effect of rapamycin on liver degeneration and 
      lifespan expansion in wild-type and HER2-neu mice. Using the model, we have 
      finally performed an in silico prospective screen of the risk-benefit ratio of 
      rapamycin dosage for healthy lifespan expansion strategies. We present here a 
      comprehensive prognostic and predictive systems biology tool for human aging.
CI  - (c) 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley 
      & Sons Ltd.
FAU - Verlingue, Loic
AU  - Verlingue L
AD  - Institut Curie, CNRS, UMR3244, Telomere and Cancer Laboratory, PSL Research 
      University, 75005, Paris, France.
AD  - Department of Medical Oncology, Institut Curie, 75005, Paris, France.
FAU - Dugourd, Aurelien
AU  - Dugourd A
AD  - Institut Curie, Mines Paris Tech, Inserm, U900, PSL Research University, F-75005, 
      Paris, France.
FAU - Stoll, Gautier
AU  - Stoll G
AD  - Sorbonne Paris Cite, Universite Paris Descartes, 12 Rue de l'Ecole de Medecine, 
      75006, Paris, France.
AD  - Equipe 11 labellisee Ligue contre le Cancer, INSERM U 1138, Centre de Recherche 
      des Cordeliers, 15 rue de l'Ecole de Medecine, 75006, Paris, France.
AD  - Universite Pierre et Marie Curie, 4 Place Jussieu, 75005, Paris, France.
FAU - Barillot, Emmanuel
AU  - Barillot E
AD  - Institut Curie, Mines Paris Tech, Inserm, U900, PSL Research University, F-75005, 
      Paris, France.
FAU - Calzone, Laurence
AU  - Calzone L
AD  - Institut Curie, Mines Paris Tech, Inserm, U900, PSL Research University, F-75005, 
      Paris, France.
FAU - Londono-Vallejo, Arturo
AU  - Londono-Vallejo A
AD  - Institut Curie, CNRS, UMR3244, Telomere and Cancer Laboratory, PSL Research 
      University, 75005, Paris, France.
AD  - UPMC Univ Paris 06, CNRS, UMR3244, Sorbonne Universites, 75005, Paris, France.
LA  - eng
GR  - ANR/
GR  - INCa/
PT  - Journal Article
DEP - 20160909
PL  - England
TA  - Aging Cell
JT  - Aging cell
JID - 101130839
PMC - PMC6398530
OTO - NOTNLM
OT  - Boolean modeling
OT  - cancer
OT  - in silico drug screening
OT  - lifespan expansion
OT  - rapamycin
OT  - type 2 diabetes mellitus
COIS- None.
EDAT- 2016/09/11 06:00
MHDA- 2016/09/11 06:01
PMCR- 2016/12/01
CRDT- 2016/09/11 06:00
PHST- 2016/06/12 00:00 [accepted]
PHST- 2016/09/11 06:00 [pubmed]
PHST- 2016/09/11 06:01 [medline]
PHST- 2016/09/11 06:00 [entrez]
PHST- 2016/12/01 00:00 [pmc-release]
AID - ACEL12504 [pii]
AID - 10.1111/acel.12504 [doi]
PST - ppublish
SO  - Aging Cell. 2016 Dec;15(6):1018-1026. doi: 10.1111/acel.12504. Epub 2016 Sep 9.